Nuclear magnetic Resonance (NMR) is an analytical technique that has seen a dramatic increase in use and development over the past few decades. The use reaches into diverse areas such as structural biology, pharmaceutics, metabolic studies, solid state chemistry, condensed matter physics, rheology and medical applications. In the latter case NMR is often used as a non-invasive imaging method, referred to as Magnetic Resonance Imaging (MRI). Advanced mathematical and physical methods, e.g. Fourier Transform (FT) and multidimensional analysis, have been incorporated into the NMR analysis methods in order to increase its usefulness and to be able to explore novel areas.
For the resonance phenomena, which is the basis of NMR and MRI, to occur, isotopes with non-zero nuclear spin have to be present. These will be referred to as NMR active nuclei in the present application. Since NMR is not a very sensitive technique, a relatively high concentration and/or a high gyromagnetic ratio is needed, especially for imaging purposes or more advanced NMR analysis e.g. two-dimensional (2D) NMR. Major attention has been given to the problem of the relatively low sensitivity of the NMR technique. Significant improvements have been achieved by the introduction of techniques for hyperpolarization of a sample, or in the case of MRI, the use of hyperpolarized contrast agents. The term hyperpolarization here refers to that non-zero spin nuclei intended to be used in the NMR analysis have been given a nuclear spin polarization, i.e., the population difference between the ground and excited states is greater than in the equilibrium distribution.
Hyperpolarization may be achieved by a number of methods known in the art. Particularly interesting methods utilize Dynamical Nuclear Polarization (DNP) through electronic spins. Such methods are disclosed in for example WO 99/35508 and WO 01/96895, by the same applicant as in the present patent application. DNP mechanisms include the Overhauser effect, the so-called solid effect and thermal mixing effect. The Overhauser effect is a relaxation driven process that occurs when the electron-nucleus interaction is time-dependent (due to thermal motion or relaxation effects) on the time scale of the inverse electron Larmor frequency or shorter, and when the electronic spins are saturated by a strong microwave irradiation. Electron-nuclear cross-relaxation results in an exchange of energy with the lattice giving rise to an enhanced nuclear polarisation. The overall enhancement depends on the relative strength of the scalar and dipolar electron-nuclear interaction and the microwave power. For static systems both thermal mixing and the solid effect are operative. In the solid effect, the electron spin system is irradiated at a frequency that corresponds to the sum or difference of the electronic and nuclear Larmor frequencies. The nuclear Zeeman reservoir absorbs or emits the energy difference and its spin temperature is modified, resulting in an enhanced nuclear polarisation. The efficiency depends on the transition probabilities of otherwise forbidden transitions that are allowed due to the mixing of nuclear states by non-secular terms of the electron-nuclear dipolar interaction. Thermal mixing arises when the electron-electron dipolar reservoir establishes thermal contact with the nuclear Zeeman reservoir. This takes place when the characteristic electronic resonance line width is of the order of the nuclear Larmor frequency. Off resonance irradiation of the electronic spins results in a cooling of the electronic spin-spin-thermal reservoir and, through thermal contact of the latter with the nuclear Zeeman energy reservoir via the electron-nuclei interactions, the nuclear polarization is enhanced. For thermal mixing both the forbidden and the allowed transitions can be involved.
The method of hyperpolarization, or in the case of MRI, the use of a hyperpolarised contrast agent, has been shown to dramatically enhance the signal recorded in the NMR analysis. This has been utilized in performing measurements that has not been possible with non-hyperpolarized samples, to lower the amount of sample needed for the analysis and to, in certain applications, dramatically shorten the measurement time needed for an analysis.
Thus, hyperpolarization, through DNP or other methods, offers a way of improving the sensitivity of NMR applications. However, the hyperpolarization does put certain requirements on how the sample is treated and how the NMR spectroscopy is performed.
One requirement arises from the condition that the hyperpolarization represent a highly non-equilibrium thermodynamic state, i.e. a hyperpolarized sample is not in thermal equilibrium.
This will cause a relaxation of the spin system towards the thermal equilibrium through a longitudinal relaxation, characterized by a parameter, T1, the longitudinal relaxation time. This is a recognized problem and measures may be taken to choose NMR active nuclei with a comparably long T1 and to further reduce the relaxation rate, for example, as taught in WO 0196895, by the same applicant as the present invention. Even if such known measures are taken, it is of highest importance to perform the NMR analysis immediately, or as soon as possible, after the hyperpolarization. This is addressed by the applications WO 0237132 and WO 0236005, by the same applicant, and are hereby incorporated by reference. In addition the NMR analysis must be relatively quick in order to be able to be performed within the relaxation time T1 of the NMR active nuclei. This is a problem in more advanced uses of NMR, for example 2D NMR and diffusion studies, wherein the NMR spectroscopy of the known methods typically takes too long to be used for a hyperpolarized sample. This is illustrated in that a standard 2D NMR study can take hours to perform, while the hyperpolarization at ambient temperature typically has a much shorter relaxation time than that.
Comparably rapid advanced NMR methods have recently been suggested, for example as described in “The acquisition of multidimensional NMR spectra within a single scan” by L. Frydman et al, Prac. Natl. Acad. Sci., 99:15858-62, Dec. 10, 2002. These methods represent major improvements regarding measurement time, but have the drawback of poor signal-to-noise ratios.
A further requirement when using hyperpolarized sample arises from the fact that the rf-pulses typically used in the NMR spectroscopy themselves affect the hyperpolarization. Many known sequences, will, if used on a hyperpolarized sample, not be able to make use of the increased signal strength possibly afforded by the hyperpolarization.
The requirements associated with the use of hyperpolarized samples maybe summarized as:                the time constraints given by the longitudinal relaxation time, require a fast NMR analysis; and        the NMR spectroscopy must be designed to avoid erasing information afforded by the hyperpolarization of the sample.        
None of the prior art methods meet these requirements.